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Published online before print February 14, 2006
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* Istituto Clinico Humanitas, Rozzano, Milan, Italy;
Mario Negri Institute for Pharmacological Research, Milan, Italy;
L. Sacco Hospital and
Centro IDET, Institute of General Pathology, University of Milan, Italy;
¶ Department of Public Health and Cell Biology, University of Rome Tor Vergata, Italy; and
|| Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy
1Correspondence: Istituto Clinico Humanitas, Via Manzoni, 56, 20089 Rozzano (Milan), Italy. E-mail: barbara.bottazzi{at}humanitas.it
ABSTRACT
The long pentraxin 3 (PTX3) is member of a complex superfamily of multifunctional proteins characterized by a cyclic multimeric structure. PTX3 is highly conserved in evolution and is produced by innate-immunity cells in response to proinflammatory signals and Toll-like receptor engagement. PTX3 plays complex, nonredundant functions in vivo, acting as a predecessor of antibodies, recognizing microbes, activating complement, facilitating pathogen recognition by phagocytes, and hence, playing a nonredundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility by acting as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional, soluble pattern recognition receptor acting as a nonredundant component of the humoral arm of innate immunity and involved in matrix deposition and female fertility.
Key Words: acute-phase protein • extracellular matrix • acute myocardial infarction
INTRODUCTION
The long pentraxin 3 (PTX3) is a member of the pentraxin superfamily, a family of proteins highly conserved during evolution and characterized by a multimeric, usually pentameric structure [1 2 3 4 ]. C-reactive protein (CRP) and serum amyloid P component (SAP) are the prototype of the pentraxin family: they are produced in the liver in response to inflammatory signals, most prominently, interleukin (IL)-6, and are acute-phase proteins in man and mouse, respectively. PTX3 is the prototype of the long pentraxin family: it shares similarities with the classical, short pentraxins but differs for the presence of an unrelated long N-terminal domain, as well as for gene organization, cellular source, and ligands recognized [3 , 4 ]. PTX3 is produced and released by a variety of cell types, including in particular, mononuclear phagocytes, dendritic cells (DC), fibroblasts, and endothelial cells in response to primary inflammatory signals and Toll-like receptor (TLR) engagement.
Two main features that characterize ptx3-deficient mice are that they are sterile and more susceptible to infections to selected pathogens [5 6 7 ]. Unlike the classic, short pentraxins CRP and SAP, whose sequence and regulation have diverged from mouse to man, PTX3 is highly conserved in evolution. Thus, results obtained using genetic approaches in the mouse are likely to be informative for the function of PTX3 in man.
The results obtained so far suggest that PTX3 plays complex, nonredundant functions in vivo, ranging from innate resistance against selected pathogens to the assembly of a hyaluronic acid (HA)-rich extracellular matrix (ECM) and female fertility [3 , 5 6 7 8 9 10 11 ]. In this review, we will summarize recent progress made in the understanding of the immunobiology and in vivo role of PTX3, and we will focus, in particular, on the effects of PTX3 interaction with some of its ligands.
CELLULAR SOURCES AND REGULATION OF PRODUCTION
PTX3 is produced rapidly and released by a variety of cell types upon exposure to primary inflammatory signals, such as tumor necrosis factor 
(TNF-) and IL-1ß, TLR ligands, and microbial moieties, such as lipopolysaccaride (LPS), lipoarabinomannans, and outer membrane proteins [3
, 4
, 11
]. Cells producing PTX3 include DC, mononuclear phagocytes, fibroblasts, endothelial cells, smooth muscle cells, adipocytes, synovial cells, and chondrocytes [12
13
14
15
16
17
18
]. Recently, PTX3 production by cells of epithelial origin, such as renal and alveolar epithelial cells, has been shown [19
, 20
].
DC are major producers of PTX3 in vitro: production is restricted to DC of the myelomonocytic lineage, whereas plasmacytoid DC are unable to produce PTX3 [12
]; conversely, PTX3 can regulate the maturation program of DC as well as the secretion of soluble factors such as IL-10 and TNF-, behaving as a flexible regulator of the functions of this cell population [21
]. PTX3 production by DC shows a unique pattern of regulation by inflammatory mediators and cytokines, and interferon-
(IFN-) and IL-10 play divergent effects. IFN-, which generally has a synergistic effect with LPS [22
], inhibits LPS induction of PTX3 in DC as well as in monocytes and endothelial cells [23
24
25
]. Conversely, IL-10 is a modest and inconsistent inducer of PTX3 in DC and monocytes [26
] but significantly amplifies the response to LPS, TLR ligands, and IL-1ß [12
, 23
]. IL-10 induces a set of genes related to tissue remodeling and is involved in the chronic and resolution phase of inflammation [27
]: PTX3 superinduction, in response to IL-10, is likely to play a role in matrix deposition, tissue repair, and remodeling. Moreover, these data suggest that besides stimulation of the humoral arm of adaptive immunity, IL-10 also stimulates the humoral arm of innate immunity.
PTX3 binds with high affinity a number of different soluble ligands, including the complement component C1q [28
, 29
], the growth factor fibroblast growth factor 2 (FGF2) [30
], the ECM protein TNF--induced protein 6 (TSG-6) [6
], and the outer membrane protein A from Klebsiella pneumoniae (KpOmpA) [11
]. Moreover, a specific interaction with apoptotic cells has been described [31
]. As detailed below, interaction of PTX3 with its ligands is fundamental for some of the physiological functions attributed to the protein (Fig. 1
).
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Ptx3 deficiency is associated with a severe defect in female fertility [5 6 7 ]. Infertility of ptx3-deficient mice is a result of an abnormal cumulus oophorus characterized by an unstable ECM in which cumulus cells are dispersed uniformly instead of radiating out from a central oocyte [6 ]. Oocytes ovulated by ptx3-deficient mice can be fertilized in vitro, indicating that the oocyte develops normally in the absence of PTX3 and that fertilization failure observed in vivo is actually a result of the defective cumulus expansion. Cumulus cells express ptx3 mRNA, and no or barely detectable expression was observed in peripheral granulosa cells [6 , 32 ]. PTX3 produced by cumulus cells localizes in the ECM, playing a crucial role in the assembly of the HA-rich matrix of the cumulus oophorus. PTX3 does not interact directly with HA, but it binds TSG-6, which participates in the assembly of the HA-rich matrix. Thereby, PTX3 may form multimolecular complexes, which can cross-link HA chains, playing a role as structural constituent of the cumulus oophorus ECM essential for female fertility.
Human cumulus cells express PTX3 as well [32 ], and PTX3 protein is present in human cumulus matrix, suggesting that this molecule might have the same role in human female fertility. Real-time polymerase chain reaction data show a higher relative abundance of PTX3 mRNA in cumulus cells from fertilized oocytes compared with cumulus cells from unfertilized oocytes, indicating in PTX3 a possible marker for oocyte quality [32 ], although this is not the case for PTX3 protein [33 ]. In addition, recent results show that pre-eclampsia is associated to elevated levels of PTX3 [34 ]. Thus, it would be important in the near future to assess the potential of PTX3 as a diagnostic in human fertility and pregnancy.
ROLE IN INNATE IMMUNITY AND INFLAMMATION
Pathogen recognition is a common feature among the members of the pentraxin family, and many efforts have been made to identify the molecular moieties recognized on the bacterial surface. PTX3 does not bind LPS as well as lipoteichoic acid, N-acetylmuramyl-L-alanyl-D-isoglutamine, exotoxin A, and enterotoxin A and B, but it binds with high affinity the recombinant KpOmpA, which binds and activates macrophages and DC in a TLR2-dependent way [11 ], activating a genetic program, which includes induction of PTX3 [35 ]. In turn, PTX3 binds KpOmpA and plays a crucial role in the amplification of the inflammatory response to this microbial protein, as demonstrated by the impairment of the inflammatory response induced by KpOmpA observed in ptx3-deficient mice [11 ].
The important role played by PTX3 in the defense against pathogens is demonstrated by the observation that ptx3-deficient mice are more susceptible to infection with selected fungal and bacterial microorganisms, such as Aspergillus fumigatus, Pseudomonas aeruginosa, and Salmonella typhymurium, while they are resistant to infection with Listeria monocytogens and Staphilococcus aureus [5 ]. These results involve recognition of specific microorganisms by PTX3: binding of PTX3 has been demonstrated for conidia of A. fumigatus as well as for P. aeruginosa and S. typhymurium, while PTX3 does not recognize L. monocytogens. Moreover, macrophages from ptx3-transgenic mice have an improved phagocytic activity toward zymosan and Paracoccidioides brasiliensis [8 ]. Also, in this case, a direct interaction of PTX3 with zymosan and P. brasiliensis has been observed. These findings provide evidences for a role of PTX3 as an opsonin and imply the existence of a receptor for this molecule: a binding site has been observed on murine macrophages as well as human mononuclear phagocytes and DC (B. Bottazzi, unpublished results).
Ptx3-transgenic and -deficient mice were used to evaluate the role of PTX3 in inflammatory conditions. Ptx3 overexpression increases resistance to LPS toxicity and cecal ligation and puncture [9 ]; moreover, ptx3-transgenic mice show an exacerbated, inflammatory response and reduced survival rate following intestinal ischemia reperfusion injury [10 ]. In a model of kainate-induced seizures, ptx3-deficient mice had more widespread and severe IL-1-induced neuronal damage. In this model, PTX3 confers resistance to neurodegeneration, possibly by binding to dying neurons and rescuing them from otherwise irreversible damage [36 ].
In humans, PTX3 blood levels are barely detectable in normal conditions and increase rapidly during a range of inflammatory and infectious conditions. In a prospective study about a large group of patients with acute myocardial infarction (AMI), PTX3 has been shown to be the stronger prognostic marker of death [37 ]. PTX3 levels are elevated in critically ill patients, reflecting the severity of disease [38 ]. Likewise, patients with active vasculitis have significantly higher plasma levels of PTX3 than patients with quiescent disease [39 ]. Higher levels of PTX3 are associated with disease severity and possibly with a clinical outcome in patients with dengue virus infections or active pulmonary tuberculosis [40 , 41 ].
CRP is a widely used marker of inflammation; in particular, CRP levels increase in AMI, possibly as a consequence of a systemic response to myocardial injury. A general characteristic emerging from studies about PTX3 blood levels in human pathology is the rapidity of its increase compared with CRP, together with a lack of correlation between levels of CRP and PTX3. It remains to be elucidated whether the correlation with outcome and severity actually reflects a role in the pathogenesis of damage, for instance, by amplifying the complement and coagulation cascades [42 , 43 ].
CONCLUDING REMARKS
PTX3, produced by DC, macrophages, and other cell types upon TLR engagement or pathogen recognition, is member of the conserved family of pentraxins. PTX3 recognizes microbial moieties, opsonizes fungi and selected bacteria, activates the classic pathway of complement cascade, and participates in the formation of ECM (Fig. 1) . Ptx3 gene targeting has unequivocally defined the role of this molecule at the crossroad among innate immunity, inflammation, matrix deposition, and female fertility. Results collected over the years about PTX3 levels in patients with a series of inflammatory and infectious disorders outline a role of this protein as a marker of pathology and prognostic factor. Thus, this long pentraxin is a multifunctional protein acting as a tuner of inflammatory reactions and representing a new marker of innate immunity and inflammation, rapidly reflecting tissue and vascular bed involvement.
ACKNOWLEDGEMENTS
This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministero Istruzione, Università e Ricerca (MIUR), and European Commission.
Received October 4, 2005; accepted December 12, 2005.
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